The possibility that gender differences may exist in opiate pharmacology has received relatively little systematic attention despite growing, albeit often anecdotal, evidence that strong male-female differences may exist in pain, its treatment by opiate and perhaps in abuse liability in humans. Whether these differences reflect biological or psychosocial factors has not been resolved. The purpose of this grant is to systematically determine in rats whether intrinsic, biological gender differences exist in opiate antinociception, physical dependence and tolerance and the reinforcing effects of these drugs. Accordingly, we have four specific aims: First, to examine whether there are sex differences in the pharmacological profile of morphine, including: its antinociceptive activity and its discriminative stimulus properties; the generation and expression of tolerance and physical dependence; and its reinforcing properties. Second, to examine whether the sex differences observed with morphine are a unique property of this opiate or are a more common feature of opiates selective for other opiate receptor sub-types, delta and/or kappa. Third, to determine whether the sex differences observed in opiate pharmacology can be explained by the 'activational' or organizational effects of sex-steroids. Steroids will be removed at two stages during early development - when they are know to exert their organizational effects on the male and female brain. In addition, adults rats will be castrated and ovariectomized to ascertain whether the acute activational effects of the sex steroids may be involved. Fourth, to examine whether the sex differences observed in opiate pharmacology can be explained solely by the metabolic or biodispositional factors rather than by intrinsic differences in the sensitivity of the nervous system to morphine. The proposed studies could be relevant to several very important clinical issues related to the abuse potential of opiates and potentially the treatment and prevention of drug abuse. Moreover, these studies could also focus on possible gender differences in the management of pain. Although there are a few studies in humans suggesting gender differences in the abuse liability of drugs, in prevention and treatment of outcomes and pain management, there have been few systematic studies examining whether these differences are related to biological factors or reflect a possible artifact related to a host of psychosocial variables. The proposed animal studies could establish whether gender differences exist and if these differences are based on inherent, first-order biological differences between the sexes.